Soluble compounds

Abstract

The present invention relates to a tertiary amide compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 7 contains an X group that is -S(=O)2OH, -S(=O)OH, or -P(=O)(OH)2. The compounds can solubilize otherwise insoluble drugs. By enhancing the solubility of poorly soluble or insoluble drugs, such as hydrophobic drugs, the compounds of the invention enable the preparation of formulations of such drugs. The invention also relates to pharmaceutical compositions comprising a compound of Formula (I), drug micelles comprising a compound of Formula (I) and a drug, and the use of such pharmaceutical compositions or drug micelles in the treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to a tertiary amide compound of formula (I), or a pharmaceutically acceptable salt thereof. The compound can solubilize otherwise insoluble drugs. By enhancing the solubility of poorly soluble or insoluble drugs, such as hydrophobic drugs, the compounds of the invention enable the preparation of formulations of such drugs. The invention also relates to pharmaceutical compositions comprising the compound of formula (I), drug micelles comprising the compound of formula (I) and a drug, and the use of such pharmaceutical compositions or drug micelles in the treatment of cancer. [Background technology]

[0002] Many important pharmaceuticals are poorly soluble in water, typical examples being the cytostatic compounds in the taxane class (paclitaxel, docetaxel, and cabazitaxel), whose lack of solubility complicates intravenous administration.

[0003] Although several solutions to the solubility problem have been disclosed in the literature, none are without drawbacks. A good solubilizer should be non-toxic, stable, cost-effective, and easy to handle. Solubilizers may also affect the pharmacokinetics and pharmacodynamics of the active ingredient in desirable or undesirable ways, depending on the clinical situation at hand. Ideally, a solubilizer enhances the efficacy of the active ingredient while minimizing side effects.

[0004] WO 00 / 47589, WO 02 / 092600, and WO 2004 / 009538 disclose retinol derivatives that can form micelles and enhance the efficacy of cytotoxic drugs. More recently, WO 2021 / 008516 discloses acitretin derivatives that can encapsulate insoluble drugs, and the formed micelles have high drug loading capacity and good stability.

[0005] Despite previous advances in this field, there continues to be a need for additional compounds that can solubilize poorly soluble drugs and provide stable formulations of such drugs. It is therefore an object of the present invention to provide additional solubilizing compounds that have an optimized profile with respect to desired properties, such as micelle-forming properties and stability of micelle formulations. Summary of the Invention

[0006] The inventors have developed retinoyl derivatives useful, for example, in pharmaceutical formulations with poorly water-soluble drugs. Examples 1-10 demonstrate the synthesis and characterization of 10 different compounds within the general formula described in more detail below. The examples also characterize pharmaceutical formulations with novel compounds and drugs. Using docetaxel, cabazitaxel, and cyclosporine as model compounds, the inventors demonstrate stable micellar formulations of compounds and drugs.

[0007] The invention is described in detail below. Certain main aspects of the invention are defined in the accompanying independent claims. Certain preferred embodiments are presented in the dependent claims. Detailed Description

[0008] In a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is [ka] and; R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-4alkoxycarbonyl; join [ka] is either cis or trans; R 6 is a halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, aminocarbonyl-C 1-4 and phenyl, wherein phenyl is optionally selected from the group consisting of halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; R 7 Ha-(CR 8A R 8B ) n -X, benzyl-X or C 3-7 -cycloalkyl-(CR 8A R 8B ) m -X, n is an integer 2 or 3, m is an integer 1 or 2, and benzyl may optionally further comprise halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; or R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, where p is an integer 1 or 2, and phenyl or benzoyl may optionally further be substituted with halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; R 8A and R 8B are each independently hydrogen, hydroxy, C 1-4 Alkyl, C 1-4 selected from the group consisting of alkoxy, —S(═O)OH, —S(═O)OH, and —P(═O)(OH); and X is -S(=O)2OH, -S(=O)OH, or -P(=O)(OH)2.

[0009] In a more preferred embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-4 alkoxycarbonyl; R 6 is a halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, aminocarbonyl-C 1-4 and phenyl, wherein phenyl is optionally selected from the group consisting of halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; R 7 Ha-(CR 8A R 8B ) n -X, benzyl-X or C 3-7 -cycloalkyl-(CR8A R 8B ) m -X, n is an integer 2 or 3, m is an integer 1 or 2, and benzyl may optionally further comprise halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; or R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, where p is an integer 1 or 2, and phenyl or benzoyl may optionally further be substituted with halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; R 8A and R 8B are each independently hydrogen, hydroxy, C 1-4 Alkyl, C 1-4 selected from the group consisting of alkoxy, —S(═O)OH, —S(═O)OH, and —P(═O)(OH); and X is -S(=O)2OH, -S(=O)OH, or -P(=O)(OH)2.

[0010] In some embodiments, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, and methoxy. 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, and methoxy. 1 , R 2 and R 5 are each methyl, and R 3is methoxy and R 4 is hydrogen.

[0011] In some embodiments, R 6 is C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl and aminocarbonyl-C 1-4 In some embodiments, R 6 is methyl, 2-hydroxyethyl, cyclohexyl, prop-2-enoyl, 1,1-bis(hydroxymethyl)-2-hydroxyethyl, or aminocarbonylmethyl. In some embodiments, R 6 is methyl, 2-hydroxyethyl, cyclohexyl, or aminocarbonylmethyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is cyclohexyl.

[0012] In some embodiments, R 7 Ha-(CR 8A R 8B ) n -X, n is an integer 2 or 3, and R 8A and R 8B are each independently hydrogen, hydroxy, C 1-4 Alkyl and C 1-4 In a more preferred embodiment, R 7 Ha-(CR 8A R 8B ) n -X, n is an integer 2 or 3, and R 8A and R 8B are each independently selected from the group consisting of hydrogen and hydroxy.

[0013] In some embodiments, R 7is benzyl-X, wherein benzyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and amino. 7 is benzyl-X, where the benzyl is further substituted with amino.

[0014] In some embodiments, R 7 is C 3-7 -cycloalkyl-(CR 8A R 8B ) m -X, m is an integer 1 or 2, and R 8A and R 8B are each independently selected from the group consisting of hydrogen and hydroxy. 7 is cyclohexyl-methyl-X.

[0015] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a six-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, where p is an integer 1 or 2. In a more preferred embodiment, R 6 and R 7 together with the nitrogen atom to which they are attached form a piperidine or piperazine ring, which is substituted with ethyl-X, phenyl-X, or benzoyl-X. In some embodiments, X is —S(═O)OH.

[0016] In a more preferred embodiment, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, and methoxy; R 6is methyl, 2-hydroxyethyl, cyclohexyl, or aminocarbonylmethyl; and X is -S(=O)2OH.

[0017] In some embodiments, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C(=O)OR 10 R 10 is C 1-4 is alkyl; R 6 is a halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl, C 3-8 cycloalkylcarbonyl, -C(=NH)NH2, and phenyl, wherein phenyl is optionally selected from the group consisting of halogen, hydroxy, C 1-4 Alkyl, C 1-4 substituted with one or more substituents selected from the group consisting of alkoxy and amino; Each R 9 are independently hydrogen, hydroxy, C 1-4 Alkyl, C 1-4 alkoxy, —S(═O)OH, —S(═O)OH, and —P(═O)(OH) or R 6 and R 9 one of which forms a piperidine ring together with the atoms attached to them; Each R 10 are independently hydrogen, hydroxy, C1-4 Alkyl, C 1-4 selected from the group consisting of alkoxy, -S(=O)2OH, -S(=O)OH and -P(=O)(OH); Each R 11 are independently hydrogen, hydroxy, C 1-4 Alkyl, C 1-4 selected from the group consisting of alkoxy, -S(=O)2OH, S(=O)OH and -P(=O)(OH)2; n is an integer 0 or 1; and X is -S(=O)2OH, -S(=O)OH, or -P(=O)(OH)2.

[0018] In some embodiments, the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, and methoxy; R 6 is methyl, cyclohexyl, prop-2-enoyl or 1,1-bis(hydroxymethyl)-2-hydroxyethyl; Each R 9 is independently selected from the group consisting of hydrogen and methyl; R 10 is hydrogen or hydroxy; and n is an integer of 0 or 1.

[0019] In some embodiments of Formula (III), R 1 , R 2 and R 5 are each methyl, and R 3 is methoxy and R 4 is hydrogen.

[0020] In certain embodiments, the present invention relates to a compound selected from the group consisting of: [ka] TIFF2025531447000009.tif56159

[0021] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo.

[0022] In this specification, "C 1-6 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and "C 1-4 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. 1-4 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0023] In this specification, "C 2-4 The term "alkenyl" refers to a straight or branched chain alkenyl group having 2 to 4 carbon atoms and at least one double bond. 2-4 Examples of alkenyl include ethenyl (vinyl), allyl, and 1,3-butadienyl.

[0024] In this specification, "C 1-6 The term "haloalkyl" refers to a straight or branched C alkyl group, as defined herein, in which one or more of the hydrogen atoms are replaced with a halogen. 1-6 Indicates an alkyl group. C 1-6 Examples of haloalkyl include chloromethyl, fluoroethyl, and trifluoromethyl.

[0025] In this specification, "C 1-4 The term "hydroxyalkyl" refers to a straight or branched C alkyl group, as defined herein, in which one or more of the hydrogen atoms have been replaced with a hydroxy group (-OH).1-4 Indicates an alkyl group. C 1-4 Examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, and 1,1-bis(hydroxymethyl)-2-hydroxyethyl.

[0026] In this specification, "C 1-4 The term "alkoxy" refers to a straight or branched C alkyl group attached to the rest of the molecule through an oxygen atom. 1-4 represents an alkyl group.

[0027] In this specification, "C 3-8 The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 8 carbon atoms. 3-8 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028] In this specification, "C 1-4 The term "alkylcarbonyl" refers to a straight or branched C alkyl group, as defined herein, attached to a carbonyl group. 1-4 Indicates an alkyl group. 2-4 alkenylcarbonyl" and "C 3-8 The term "cycloalkylcarbonyl" should be construed accordingly. 1-4 Examples of alkylcarbonyl include ethylcarbonyl and tert-butylcarbonyl. 2-4 Examples of alkenylcarbonyl include prop-2-enoyl (acryloyl). 3-8 Examples of cycloalkylcarbonyl include cyclopropylcarbonyl and cyclohexylcarbonyl.

[0029] Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, base addition salts of the compounds of the invention, such as alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); ammonium salts; basic amino acids (e.g., arginine, lysine, histidine); betaine; or salts with organic bases which provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trialkylamines (e.g., trimethylamine), piperidine, pyrrolidine, morpholine, choline, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS) or triethanolamine (tris-(2-hydroxyethyl)amine).

[0030] Pharmaceutical Composition Unless otherwise specified, references herein to compounds of formula (I) should be understood to also include compounds of formulas (II) and (III).

[0031] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition also optionally comprises one or more pharmaceutically acceptable excipients. Excipients include, for example, water, aqueous buffer, saline, cosolvents, fillers, binders, disintegrants, glidants and lubricants. In general, pharmaceutical compositions can be prepared in a conventional manner using conventional excipients.

[0032] Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, and polyethylene glycol (eg, PEG400).

[0033] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0034] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia gum, xanthan gum, tragacanth gum, and carrageenan), sodium alginate, cellulose derivatives (e.g., hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, and ethyl cellulose), and synthetic polymers (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0035] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (e.g., (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g., sodium carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)), and cross-linked polymers (e.g., carmellose, croscarmellose sodium, carmellose calcium, and cross-linked PVP (crospovidone)).

[0036] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silica, aqueous silicon dioxide, synthetic magnesium silicate, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (e.g., carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0037] The pharmaceutical composition may be in a form suitable for oral administration, parenteral administration (e.g., intradermal, intradermal, intravenous, subcutaneous, intramuscular, intraperitoneal, and intravascular injection or infusion), topical administration, ophthalmic administration, oral administration (e.g., sublingual administration), nasal administration (e.g., inhalation), or rectal administration. In a preferred embodiment, the pharmaceutical composition is in the form of a liquid formulation suitable for oral or parenteral administration. In another embodiment, the pharmaceutical composition is in the form of a solid formulation suitable for oral administration, such as a tablet or capsule. In yet another embodiment, the pharmaceutical composition is in the form of a formulation suitable for topical administration, such as an ointment or cream.

[0038] In some embodiments, the pharmaceutical composition further comprises at least one active active ingredient (also referred to herein as a "drug" or "API"). In some embodiments, the composition comprises more than one active active ingredient. The active active ingredient may be a small molecule, a macromolecule, a peptide, a protein (e.g., an enzyme), a nucleic acid, an antigen, an antibody, or a viral vector. As demonstrated in the experimental section, the compounds of the invention form micelles that can encapsulate or contain the active active ingredient within the micellar structure. This enhances the solubility of otherwise poorly soluble or insoluble drugs, enabling the preparation of pharmaceutical formulations containing poorly soluble or insoluble drugs. Such formulations of poorly soluble or insoluble drugs also allow the drug to be administered in a liquid formulation. In addition, such formulations can increase the bioavailability of the drug.

[0039] Pharmaceutical compositions comprising an active ingredient (e.g., a poorly soluble or insoluble drug) and at least one compound of Formula (I) can further exhibit enhanced pharmacological activity and / or improved therapeutic efficacy. Such compositions can also enhance distribution of the drug to the target tissue(s), potentially reducing undesirable side effects. Such compositions can also improve the pharmacokinetic properties of the active ingredient, such as elimination half-life, maximum plasma concentration, clearance, volume of distribution, and / or mean residence time.

[0040] In some embodiments, the active ingredient is a hydrophobic drug. Such drugs may be characterized, for example, by having a water solubility of less than 100 μg / mL at 20° C.

[0041] In some embodiments, the active ingredient is a macrocyclic drug, e.g., a macrolide, a macrocyclic peptide, or a metallo-supramolecular compound, such as cyclosporine, rifamycin, rapamycin, vancomycin, dactinomycin, amphotericin B, ivermectin, simeprevir, ixabepilone, sirolimus, or tacrolimus.

[0042] In some embodiments, the active ingredient is a cytotoxic drug, e.g., a taxane, such as docetaxel, paclitaxel, or cabazitaxel; an anthracycline, such as aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, or zorubicin; an anthracenedione, such as mitoxantrone, losoxantrone, pixantrone, amsacrine, or bisantrene; or a vinca alkaloid, such as vinblastine, vincristine, vindesine, vinflunine, or vinorelbine.

[0043] Also provided herein are drug micelles comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a drug. In some embodiments, the drug is a hydrophobic drug. In some embodiments, the drug is a cytotoxic drug. In some embodiments, the cytotoxic drug is selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, doxorubicin, and mitoxantrone.

[0044] In some embodiments, the compound of Formula (I) and the drug are present in the composition in a ratio of about 20:1 to about 1:20 (w / w), such as about 15:1 to about 1:15, or such as about 10:1 to about 1:10. In some embodiments, the compound of Formula (I) and the hydrophobic drug are present in the micelle in a ratio of about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10 (w / w).

[0045] The particle size of the micelles in the composition typically ranges from about 5 to about 150 nm, and can be determined, for example, using dynamic light scattering (DLS) at a drug concentration of 1 mg / mL in 0.9% NaCl, preferably using a red laser with a wavelength of 633 nm.

[0046] It has been found that the particle size depends on the properties of the compound of formula (I) and the drug, the ratio between the compound of formula (I) and the drug, and the concentration of the compound in the composition. By varying these conditions, the particle size of the micelles can be adjusted as desired. Depending on the situation, the micelles may be in equilibrium with the "free" compound of formula (I), or a pharmaceutically acceptable salt thereof, and / or the "free" drug. Alternatively, the micelles may reform over time. Thus, the particle size (and, consequently, the polydispersity index) may change somewhat over time after micelle formation, for example, after 4 hours, 8 hours, 12 hours, or 24 hours. In some embodiments, the particle size is about 5 to about 125 nm, e.g., about 25 to about 125 nm, about 50 to about 125 nm, about 75 to about 125 nm, or about 100 to 125 nm; e.g., about 25 to about 100 nm, about 25 to about 75 nm, or about 25 to about 50 nm; or for example, about 50 to 100 nm, about 50 to about 75 nm, or about 75 to 100 nm. Preferably, the particle size is less than 100 nm. Preferably, the polydispersity index is less than 0.5, more preferably less than 0.4, and even more preferably less than 0.3. In some embodiments, the polydispersity index is 0 to 0.5, e.g., 0 to 0.4, or e.g., 0 to 0.3. Preferably, the particle size distribution is substantially unimodal.

[0047] Methods and Uses In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and a drug, for use in therapy.

[0048] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and a cytotoxic agent, for use in the treatment of cancer.

[0049] In another aspect, the present invention relates to a cytotoxic drug micelle comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and a cytotoxic drug, for use in the treatment of cancer.

[0050] The invention also relates to the use of said pharmaceutical composition or said cytotoxic drug micelle in the manufacture of a medicament for the treatment of cancer.The invention also relates to a method of treating cancer in a subject, e.g., a human, comprising administering to a subject in need of such treatment a therapeutically effective amount of said pharmaceutical composition or said cytotoxic drug micelle.

[0051] Also provided herein is a method for enhancing the effectiveness of a pharmaceutically active agent, wherein said agent is prepared in a micellar form with at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0052] Also provided herein is a method for increasing the solubility of a pharmaceutically active agent, wherein said agent is prepared in a micellar form with at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0053] Also provided herein is a method for improving the pharmacokinetic or pharmacodynamic properties of a pharmaceutically active agent, wherein said agent is formulated in a micellar form with at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0054] Also provided herein is a method for improving the storage properties of a pharmaceutically active substance, wherein said substance is prepared in a micellar form with at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0055] radioactive isotope In another aspect, the invention also relates to a compound of formula (I), (II) or (III) as defined herein, wherein the compound contains at least one atom of a halogen radioisotope (radioisotope).

[0056] Preferably, R 1 , R 2 , R 3 , R 4 and R 5 At least one of R is a halogen radioisotope (radioisotope). 1 , R2 , R 3 , R 4 and R 5 One, two, three or four of the above are halogen radioisotopes, and the others are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C(=O)OR 10 wherein R 10 is C 1-4 In some embodiments, R 1 , R 2 , R 3 , R 4 and R 5 In some embodiments, one, two, three, or four of R are halogen radioisotopes, and the others are each independently selected from the group consisting of hydrogen, methyl, and methoxy. 1 , R 2 , R 3 , R 4 and R 5 are all halogen radioisotopes. Specific examples of halogen radioisotopes include fluorine-18, iodine-123, iodine-125, and iodine-131.

[0057] Compounds of formula (I) labelled with radioisotopes may be useful as radiopharmaceuticals for either diagnostic or therapeutic purposes.

[0058] definition As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for human pharmaceutical use and are generally safe, non-toxic, and not biologically or otherwise undesirable.

[0059] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or preventing the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered in a susceptible person prior to the onset of symptoms (e.g., taking into account a history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0060] The term "comprising" should be interpreted as including, but not limited to. All references are hereby incorporated by reference. The arrangement of this disclosure into sections with headings and subheadings is for ease of reading only and should not be interpreted as limiting in any way. In particular, the division does not in any way exclude or restrict the combining of features under different headings and subheadings with each other.

[0061] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments directed to that value or parameter per se. For example, a description of "about 20" includes the description "20." Numerical ranges include the numbers defining the range. Generally speaking, the term "about" refers to the indicated value of the variable, and all values ​​of the variable that are within experimental error of the indicated value (e.g., within a 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.

[0062] Example The invention will now be described by the following examples, which should not be construed as limiting the invention in any way.

[0063] Abbreviation API Active Ingredient Boc tert-butyloxycarbonyl CAPS 3-(cyclohexylamino)-1-propanesulfonic acid CAPSO 3-(Cyclohexylamino)-2-hydroxy-1-propanesulfonic acid CHES 2-(cyclohexylamino)ethanesulfonic acid DCM dichloromethane DIPEA N,N-Diisopropylethylamine DLS Dynamic Light Scattering DMF Dimethylformamide MTBE Methyl tert-butyl ether PyBOP Benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate RSD relative standard deviation SDS Sodium dodecyl sulfate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

[0064] Experimental Method Reagents and solvents were purchased from Sigma-Aldrich (Merck) or Biosynth. Room temperature indicates 20-25° C. Solvent mixture compositions are given as volume percentages or volume ratios.

[0065] 1 H NMR spectra were recorded at 500 MHz using a Variant Unity-500 spectrometer or at 300 MHz using a Bruker spectrometer. DMSO-d6 was used as the solvent.

[0066] Mass spectrometer measurements were recorded using a Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC-Mass Spectrometer equipped with a DAD detector.

[0067] Merck silica gel RP-18 plates were used for thin-layer chromatography (TLC) and developed with a solvent system consisting of methanol:water (7:3, v / v).

[0068] Micelle size was measured using a ZetaSizer from Malvern Panalytical.

[0069] HPLC was performed on a Chromaster HPLC system (Hitachi). Analysis was performed using a Hypurity C18 column, 250 x 4.6 mm, 3.0 μm (Thermo Scientific). Mobile phase: Solvent A: 10% NHOAc(aq), 10% SDS(aq) and 80% acetonitrile, Solvent B: 10% NHOAc(aq), 10% SDS(aq) and 80% water. Flow rate: 1 mL / min. Run time: 65 min. Pump program: [Table 1]

[0070] Example 1 1.1 Synthesis of Compound 1 [ka] In a 25 mL two-neck flask, acitretin (250 mg, 0.77 mmol) and TEA (92 μL, 0.91 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10° C. A solution of isobutyl chloroformate (129 μL, 0.99 mmol) in THF (0.5 mL) was added dropwise to the cooled solution. The resulting mixture was stirred for 30 min at 5-10° C. under inert conditions and protected from light.

[0071] A solution of CHES (222 mg, 1.07 mmol) and TEA (149 μL, 1.07 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2.5 h. Acetic acid (200 μL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (300 mg) was carefully added to the aqueous layer. When the effervescence ceased, brine (20 mL, 25% NaCl solution) was added, and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (20 mL, 12.5% ​​NaCl solution) and methanol (2 mL). The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure (40-70 mbar, 39 °C). The vacuum was released with inert gas (N2). The product was washed with MTBE (10 mL) and dried under vacuum. The obtained product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give the product as a yellow solid (purity 94.8%). Yield: 50%.

[0072] 1 H NMR (500MHz, DMSO-d6): δ6.85(ddd, 1H, J=30.2, 15.2, 11.4Hz, CH=CH-);6.67(s, 1H, Ph-H);6.65(d, 1H, J=16.4Hz, -CH=CH-);6. 42(dd, 1H, J=16.4Hz, -CH=CH-);6.31(s, 1H, =C-CH);6.25-6.19(m, 2H, -CH=CH-);3.78(s, 3H, -O-CH3);3.45(m, 2H, CH2);3.35( m, 2H, CH2); 2.65 (m, 1H, CHcyclohexyl); 2.50 (s, 3H, CH3); 2.23 (s, 3H, CH3); 2.21 (s, 3H, CH3); 2.12 (s, 6H, CH3); 1.9 (s, 3H, CH3); 1.77, (m, a(2H)cyclohexyl); 1.62, (m, e(2H)cyclohexyl); 1.28, (m, a(2H)cyclohexyl); 1.10, (m, e(2H)cyclohexyl); 1.05, (m, 2H, cyclohexyl). m / z=538.26;516.27.

[0073] 1.2. Formulations with API 1.2.1 Docetaxel-containing formulations 3.8 mg of Compound 1 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (2 mL). 240 μL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.2 mL). Finally, 0.9% sodium chloride solution (1.0 mL) was added to obtain a final yellow, clear solution. The drug loading capacity is defined as the ratio of API:(API + excipients). [Table 2]

[0074] 20 mg of Example 1 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (3 mL). 800 μL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a docetaxel concentration of 4 mg / mL. The 4 mg / mL concentration was further diluted with 0.9% sodium chloride according to the table below. [Table 3]

[0075] 11 mg of Example 1 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (2 mL). 740 μL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding 0.9% sodium chloride to a concentration of 1 mg / mL docetaxel, resulting in a yellow, clear solution. [Table 4]

[0076] A stock solution of docetaxel in methanol was mixed with a stock solution of Compound 1 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:5. Particle size and polydispersity index measurements were performed over time as shown in the table below. A small increase in particle size and polydispersity index over time was recorded. The changes were within acceptable limits. [Table 5]

[0077] Serial dilutions were performed on the docetaxel:Compound 1 system. A stock solution of docetaxel in methanol was mixed with a stock solution of the micelle-forming agent (Compound 1) in a 1:5 weight ratio in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a docetaxel concentration of 1 mg / mL. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution. The micelle size and RSD showed no significant trends during dilution. [Table 6]

[0078] 1.2.2 Preparations containing cabazitaxel 4.5 mg of compound 1 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (2 mL). 1500 μL of a stock solution of cabazitaxel in methanol (1.00 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding 0.9% sodium chloride to a concentration of 1 mg / mL cabazitaxel, resulting in a yellow, clear solution. The results for different dilutions are shown in the table below. [Table 7]

[0079] 1.2.3 Preparations containing cyclosporine 4.5 mg of compound 1 was dispensed into a 25 mL round-bottom flask and dissolved in 2 mL of methanol. 1500 μL of a stock solution of cyclosporine in methanol (1.00 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. Hydration of the dried film was performed by adding 0.9% sodium chloride to a concentration of 1 mg / mL cyclosporine, resulting in a yellow, clear solution. The results for different dilutions are shown in the table below. [Table 8]

[0080] A stock solution of cyclosporine in methanol was mixed with a stock solution of Compound 1 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL cyclosporine. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a concentration of 0.5 mg / mL cyclosporine. The final weight ratio of cyclosporine to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time as shown in the table below. A small increase in particle size and a change in polydispersity index were recorded over time. The changes were within acceptable limits. [Table 9]

[0081] Example 2 2.1 Synthesis of Compound 2 [ka] In a 25 mL two-neck flask, acitretin (500 mg, 1.5 mmol) and TEA (216 μL, 1.68 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10° C. A solution of isobutyl chloroformate (260 μL, 1.97 mmol) in THF (0.5 mL) was added dropwise to the cooled solution. The resulting mixture was stirred for 30 min at 5-10° C. under inert conditions and protected from light.

[0082] A solution of CAPS (475 mg, 2.14 mmol) and TEA (276 μL, 2.14 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2 hours. Acetic acid (600 μL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (600 mg) was carefully added to the aqueous layer. When effervescence ceased, brine (20 mL of 25% NaCl solution) was added, and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (20 mL of 12.5% ​​NaCl solution) and methanol (1-3 mL). The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure (40-70 mbar at 39 °C). The vacuum was released with inert gas (N2). The resulting product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give a yellow product (purity 88.2%). Yield: 10%.

[0083] 1H NMR (500MHz, DMSO-d6): δ6.75(m, 1H, CH=CH-); 6.70(s, 1H, Ph-H); 6.65(m, 1H, -CH=CH-); 6.45(dd , 1H, -CH=CH-);6.27(s, 1H, C=CH-);6.20-6.25(m, 2H, -CH=CH-);3.75(s, 3H, -O-CH3);3.40-3.35 (m, 4H, CH2); 3.48 (m, 2H,); 2.60 (m, (1H) cyclohexyl); 2.26 (s, 3H, CH3); 2.05 (s, 3H, CH3); 1.95 (s, 3H, CH3); 1.75 (s, 6H, CH3); 1.55 (m, 6H, cyclohexyl); 1.25 (m, 2H, cyclohexyl); 1.14 (m, 2H, cyclohexyl).

[0084] 2.2 Formulations with API 2.2.1 Docetaxel-containing formulations 4.0 mg of compound 2 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (3 mL). 250 μL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.25 mL). This solution was mixed 1:1 v / v with 0.9% sodium chloride solution to obtain a final yellow, clear solution. The results are shown below. [Table 10]

[0085] Example 3 3.1 Synthesis of Compound 3 [ka] In a 25 mL two-neck flask, acitretin (500 mg, 1.53 mmol) and TEA (236 μL, 1.80 mmol) were dissolved in anhydrous THF (15 mL), and the reaction mixture was cooled to 5-10° C. A solution of isobutyl chloroformate (260 μL, 1.97 mmol) in THF (0.8 mL) was added dropwise to the cooled solution. The resulting mixture was stirred for 30 min at 5-10° C. under inert conditions and protected from light.

[0086] A solution of 2-(methylamino)ethane-1-sulfonic acid (298 mg, 2.14 mmol) and TEA (286 μL, 2.17 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2.5 hours. Acetic acid (500 μL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (400 mg) was carefully added to the aqueous layer. When effervescence ceased, brine (20 mL of 25% NaCl solution) was added, and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (20 mL of 12.5% ​​NaCl solution) and methanol (1-3 mL). The aqueous layer was discarded and the organic layer was evaporated under reduced pressure (40-70 mbar at 39°C). The vacuum was released with inert gas (N2). The resulting product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give the product as a yellow solid (purity 99.4%). Yield: 55%.

[0087] 1H NMR (500MHz, DMSO-d6): δ6.86(t, 1H, J=13.3Hz, CH=CH-), 6.72-6.57(m, 2H); 6.44(s, 1H, -CH=CH-); 6.32-6.18(m, 3H, -CH=CH); 3.70(s, 3 H, -O-CH3);3.70-3.50(d,2H,CH2);3.20-2.70(t,3H,N-CH3);2.70-2.67(d,CH2);2.25(s,3H,CH3);2.24(s,3H,CH3);2.07(s,9H,CH3). m / z = 470.19; 448.21.

[0088] 3.2 Formulations with API 3.2.1 Docetaxel-containing formulations 4.5 mg of compound 3 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (3 mL). 305 μL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (1.5 mL), resulting in a clear yellow solution. The results for different dilutions are shown in the table below. [Table 11]

[0089] 4.5 mg of compound 3 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (3 mL). 0.455 μL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (2.25 mL), resulting in a clear yellow solution. The results for different dilutions are shown in the table below. [Table 12]

[0090] A stock solution of docetaxel in methanol was mixed with a stock solution of Compound 3 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time as shown in the table below. Small changes in particle size and polydispersity index were recorded over time. The changes were within acceptable limits. [Table 13]

[0091] 3.2.2 Preparations containing cyclosporine A stock solution of cyclosporine in methanol was mixed with a stock solution of compound 3 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL cyclosporine. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a concentration of 0.5 mg / mL cyclosporine. The final weight ratio of cyclosporine to micelle-forming agent was 1:3. Measurements of particle size and polydispersity index were performed over time as shown in the table below. Small changes in particle size and polydispersity index were recorded over time (see table below). The changes were within acceptable limits. [Table 14]

[0092] Example 4 4.1 Synthesis of Compound 4 [ka] In a 25 mL two-neck flask, acitretin (250 mg, 0.77 mmol) and TEA (95 μL, 0.80 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10 °C. A solution of isobutyl chloroformate (129 μL, 1.0 mmol) in THF (0.5 mL) was added dropwise to the cooled solution. The resulting mixture was stirred for 30 minutes at 5-10 °C under inert conditions and protected from light. A solution of CAPSO (260 mg, 1.1 mmol) and TEA (149 μL, 1.16 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred for 2 hours at room temperature under inert conditions. Acetic acid (400 μL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (300 mg) was carefully added to the aqueous layer. When the effervescence ceased, brine (25% NaCl solution, 20 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (12.5% ​​NaCl solution, 20 mL) and methanol (1-3 mL). The aqueous layer was discarded and the organic layer was evaporated under reduced pressure (40-70 mbar at 39 °C). The vacuum was released with inert gas (N2). The resulting product was purified by column chromatography (RP-C18; eluent MeOH / water 7:3) to give the product as a yellow solid. Yield: 35%.

[0093] 1H NMR (500MHz, DMSO-d6): δ6.90-6.75(m, 1H, CH=CH-);6.69(s, 1H, Ph-H);6.64(dd, 1H, J=16.4, 7.9Hz, -CH=CH-);6.44 (dd, 2H, J=24.0, 15.1Hz, -CH=CH-);6.20-6.30(m, 2H, -CH=CH-);3.75(s, 3H, -O-CH3);3.40-3.35(m, 4H, CH2);3.48( m, 1H, =CH); 2.50 (s, 3H, CH3); 2.25 (s, 3H, CH3); 2.22 (s, 3H, CH3); 2.15 (s, 1H, CH); 2.14 (s, 6H, CH3); 1.75, (m, a(2H)cyclohexyl); 1.65, (m, e(2H)cyclohexyl); 1.60, (m, a(2H)cyclohexyl); 1.58, (m, a(2H)cyclohexyl); 1.25, (m, e(2H)cyclohexyl). HPLC: Rt27.03 min, 99.21%(Max); m / z=568.26;544.37.

[0094] 4.2 Formulations with API 4.2.1 Docetaxel-containing formulations 4.5 mg of compound 4 was dispensed into a round-bottom flask and dissolved in methanol (3 mL). 0.305 μL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator (40 min) to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (1.5 mL). This solution was then further diluted with 0.9% sodium chloride solution to obtain a clear yellow solution. The results for different dilutions are shown in the table below. [Table 15]

[0095] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 4 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:5. Measurements of particle size and polydispersity index were performed over time as shown in the table below. The increase in particle size and change in polydispersity index over time were recorded (see table below). [Table 16]

[0096] Example 5 5.1 Synthesis of Compound 5 [ka] Acitretin (250 mg, 0.77 mmol) was suspended in DMF (2.5 mL), and N-(2-acetamido)-taurine (140 mg, 0.77 mmol) was added, followed by DIPEA (400 μL, 2.3 mmol). The yellow suspension was cooled to 15 °C, and PyBOP (478 mg, 0.9 mmol) was added. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was poured into cold water (10 mL), acidified to pH 1 with 1 M HCl, and extracted with EtOAc (3 × 15 mL). UPLC showed no product in the organic extract, so the organic layer was discarded. The aqueous layer was saturated with solid NaCl. After several minutes, a yellow solid precipitated. The suspension was sonicated for 1 min and then stirred at room temperature for 15 min. The solid was filtered, washed with a small amount of water, and dried under vacuum to give 240 mg of the product as a yellow solid (99.9% purity).

[0097] 235 mg of the solid was dissolved in MeOH (5 mL), and then a solution of NaOH (19 mg) in MeOH (0.5 mL) was added. The solution was stirred for 1 hour, and a yellow solid precipitated. The mixture was concentrated to approximately 3 mL, stirred for 30 minutes, and then filtered. The solid was washed with a small amount of MeOH and dried. Yield: 41% (160 mg).

[0098] 1 H NMR (300MHz, DMSO-d6): δ7.51(d, J=9.5Hz, 1H), 7.14-6.79(m, 2H), 6.66(d, J=19.1Hz, 2H), 6.45-5.94(m, 4H), 3.90(d, J=31.6Hz) , 2H), 3.76(s, 3H), 3.56(dt, J=23.1, 7.4Hz, 2H), 2.66(dt, J=13.9, 7.0Hz, 2H), 2.26(s, 3H), 2.19(s, 3H), 2.06(d, J=6.8Hz, 9H). m / z = 513.19; 491.41.

[0099] 5.2 Formulations with API 5.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 5 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time as shown in the table below. An increase in particle size and very little change in polydispersity index were recorded over time. [Table 17]

[0100] 5.2.2 Formulations containing cabazitaxel A stock solution of cabazitaxel in methanol was mixed with a stock solution of Compound 5 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a cabazitaxel concentration of 1 mg / mL. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a cabazitaxel concentration of 0.5 mg / mL. The final weight ratio of cabazitaxel to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time as shown in the table below. Small changes in particle size and polydispersity index were recorded over time (see table below). [Table 18]

[0101] Example 6 6.1 Synthesis of Compound 6 [ka] Acitretin (300 mg, 0.92 mmol) was suspended in DMF (3 mL), and DIPEA (380 μL, 2.9 mmol) was added, followed by PyBOP (622 mg, 1.2 mmol). The red solution was stirred at room temperature for 15 min, and 4-(piperazin-1-yl)benzene-1-sulfonic acid (223 mg, 0.92 mmol) was added. The resulting mixture was stirred at room temperature for 24 h. UPLC showed 93% conversion to the product. The reaction mixture was poured into cold water (20 mL), acidified to pH 1 with 1 M HCl, and treated with EtOAc, which resulted in the precipitation of an oily solid. The mixture was then saturated with solid NaCl. The organic solvent was evaporated, and the remaining aqueous suspension was stirred at room temperature for 20 min. The precipitated solid was filtered, washed twice with water, and dried under vacuum to give 575 mg of solid (purity >91%). The crude product was treated with EtOAc (15 mL) for 1 h at room temperature, and then the mixture was centrifuged. The solvent was decanted, and the residue was washed with EtOAc and centrifuged again. The contents were poured into a flask and dried to give 365 mg of a beige solid (purity >98%).

[0102] 360 mg of the solid was suspended in MeOH (20 mL), and then a solution of NaOH (49 mg) in MeOH (1.5 mL) was added to give a clear yellow solution. The solution was concentrated, and the residue was triturated with MeOH (approximately 8 mL) at room temperature for 1.5 hours. The precipitated solid was filtered, washed with MeOH, and dried under vacuum (purity 99.5%). Yield: 21% (110 mg).

[0103] 1 H NMR (300MHz, DMSO-d6): δ7.49-7.41(m, 2H), 6.96-6.82(m, 3H), 6.67(d, J=17.1Hz, 2H), 6.47(d, J=15.1Hz, 1H), 6.28(dd, J=15.8, 3.6Hz, 3H), 3.76(s, 3H), 3.69-3.55(m, 4H), 3.22-3.09(m, 4H), 2.26(s, 3H), 2.19(s, 3H), 2.06(d, J=3.4Hz, 9H). m / z(M-23)=549.24.

[0104] 6.2 Formulations with API 6.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 6 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time. Small changes in particle size and polydispersity index over time were recorded (see table below). [Table 19]

[0105] Example 7 7.1 Synthesis of Compound 7 [ka] Acitretin (250 mg, 0.8 mmol) was suspended in anhydrous DMF (5 mL). DIPEA (297 mg, 2.3 mmol) was then added, followed by PyBOP (518 mg, 1.0 mmol). The reaction was stirred at room temperature under an argon atmosphere for 10 minutes, and then trans-(4-methylamino)cyclohexyl)methanesulfonic acid (159 mg, 0.8 mmol) was added in one portion. The reaction progress was monitored by UPLC (91% conversion was achieved after 24 hours).

[0106] The reaction mixture was poured into cold water (15 mL) and acidified to pH 1 with 1 M HCl. Extraction with ethyl acetate was attempted, but the phases did not separate. The organic solvent was then evaporated, and solid NaCl was added until the mixture was saturated. The solid formed was filtered, dried, and purified by column chromatography (FC, RP-C18, 30-70% aqueous MeOH, 35 min). The fractions containing the product were concentrated and then dissolved in 5 mL of MeOH containing 1.0 eq of NaOH. The mixture was stirred at room temperature for 1 h and then evaporated to dryness. The resulting powder was triturated with acetone and then dried under vacuum (0.2 mbar) at room temperature for 24 h. 180 mg of a yellow powder (purity 99.5%) was thus obtained.

[0107] 1 H NMR (300MHz, DMSO-d6): δ6.92-6.75(m, 1H), 6.72-6.58(m, 2H), 6.53-6.36(m, 1 H), 6.34-6.01(m, 2H), 4.21(d, J=8.4Hz, 1H), 3.76(s, 3H), 3.55(d, J=18.2Hz, 1H ), 2.78(d, J=21.5Hz, 3H), 2.31(dd, J=8.2, 6.0Hz, 2H), 2.26(s, 3H), 2.19(s, 3H) , 2.10-2.04(m, 6H), 1.99(d, J=8.2Hz, 3H), 1.52(d, J=20.0Hz, 5H), 1.00(s, 2H). m / z(M-23)=514.23.

[0108] 7.2 Formulations with API 7.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 7 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Particle size and polydispersity index measurements were performed over time as shown in the table below. Small changes in particle size and polydispersity index over time were recorded (see table below). [Table 20]

[0109] Example 8 8.1 Synthesis of Compound 8 [ka] Acitretin (250 mg, 0.8 mmol) was suspended in anhydrous DMF (5 mL). DIPEA (297 mg, 2.3 mmol) was then added, followed by PyBOP (518 mg, 1.0 mmol). The reaction was stirred at room temperature under an argon atmosphere for 10 minutes. 2-(piperidin-4-yl)ethane-1-sulfonic acid (148 mg, 0.8 mmol) was then added in one portion. The progress of the reaction was monitored by UPLC.

[0110] The reaction mixture was poured into cold water (15 mL) and acidified to pH 1 with 1 M HCl. The mixture was saturated with solid NaCl, but no solid formed. The solution was purified by column chromatography (FC, RP-C18, 30-70% aqueous MeOH, 35 min). The fractions containing the product were concentrated and then dissolved in 5 mL of MeOH containing 1.0 eq of NaOH. The mixture was stirred at room temperature for 1 h and then evaporated to dryness. The resulting powder was triturated with acetone and then dried under vacuum (0.2 mbar) at room temperature for 24 h. 190 mg of a yellow powder (purity 99.7%) was thus obtained.

[0111] 1 H NMR (300MHz, DMSO-d6): δ6.83(dd, J=15.2, 11.3Hz, 1H), 6.74-6.60(m, 2H), 6.43(d, J=1 5.1Hz, 1H), 6.33-6.11(m, 3H), 4.38(d, J=12.9Hz, 1H), 3.83(d, J=13.6Hz, 1H), 3.76(s, 3 H), 2.96(t, J=12.9Hz, 1H), 2.46-2.35(m, 2H), 2.26(s, 3H), 2.19(s, 3H), 2.08-2.02(m, 7 H), 1.99(d, J=1.0Hz, 3H), 1.67(d, J=12.8Hz, 2H), 1.60-1.45(m, 3H), 1.07-0.83(m, 3H). m / z = 502,19; 500.21.

[0112] 8.2 Formulations with API 8.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 8 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Measurements of particle size and polydispersity index were performed over time as shown in the table below. An increase in particle size and a small change in polydispersity index over time were recorded (see table below). [Table 21]

[0113] Example 9 9.1 Synthesis of Compound 9 Step 1: [ka] Boc-piperazine (1.0 g, 5.37 mmol) was dissolved in anhydrous DMF (10 mL) under an inert atmosphere. PyBop (3.63 g, 7.0 mmol) and DIPEA (2.81 mL, 16.1 mmol, 3.0 eq) were then added, and the reaction mixture was stirred at room temperature for 5 minutes. 4-Sulfo-benzoic acid potassium salt (1.29 g, 5.37 mmol) was then added in one portion. The reaction mixture was stirred at room temperature overnight. The precipitated product was filtered and dried. Yield: 76%.

[0114] Step 2: [ka] The compound from Step 1 (0.5 g, 1.22 mmol) was added to a mixture of TFA and DCM (1:1, 5 mL), and the reaction mixture was stirred at room temperature for 30 min. The solvent was then evaporated. MeOH (5 mL) was added, and after a while a white solid precipitated. The solid was filtered and washed with a small amount of MeOH. Yield: 0.217 g (42%); purity: 97%.

[0115] Step 3: [ka] Acitretin (100 mg, 0.31 mmol) was suspended in anhydrous DMF (2 mL) under an argon atmosphere, and DIPEA (215 μL, 1.2 mmol) and PyBop (208 mg, 0.4 mmol) were added. The reaction mixture was stirred at room temperature for 3 minutes, and then the compound from Step 2 (130 mg, 0.3 mmol) was added in one portion. The solution was stirred overnight at room temperature. The product was isolated by chromatography (RP-C18, water / MeOH). The residue was triturated with acetone to give the product as a yellow powder (purity 99.4%). Yield: 24 mg (13%).

[0116] 1 H NMR (300MHz, DMSO-d6): δ7.66(d, J=8.1Hz, 2H), 7.48-7.31(m, 2H), 6.89(dd, J=15.3, 11.4Hz, 1H), 6.67(d, J=16.9Hz, 2H) , 6.43(d, J=15.1Hz, 1H), 6.26(t, J=14.9Hz, 2H), 3.76(s, 3H), 3.55(s, 8H), 2.26(s, 3H), 2.19(s, 3H), 2.10-2.03(m, 9H). m / z = 579.29; 577.19.

[0117] 9.2 Formulations with API 9.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 9 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:3. Measurements of particle size and polydispersity index were performed over time as shown in the table below. An increase in particle size and a small change in polydispersity index were recorded over time (see table below). [Table 22]

[0118] Example 10 10.1 Synthesis of Compound 10 [ka] Acitretin (400 mg, 1.23 mmol) was suspended in DMF (4 mL), and DIPEA (640 μL, 3.7 mmol) was added, followed by PyBOP (765 mg, 1.5 mmol, 1.2 eq). The solution was stirred at room temperature for 5 minutes, and then 5-amino-2-[(2-hydroxyethylamino)-methyl]-benzenesulfonic acid (302 mg, 1.23 mmol) was added. The resulting mixture was stirred at room temperature for 21 hours. UPLC indicated 86% conversion to the product. The reaction mixture was poured into cold water (40 mL) and acidified to pH 1 with 1 M HCl. The mixture was saturated with NaCl, forming a gummy solid. The mixture was sonicated for 20 minutes and then stirred at room temperature for 30 minutes. The precipitated solid was centrifuged. The solvent was decanted, and the residue was washed with water (15 mL) and centrifuged again. The washing and centrifugation procedure was then repeated twice. The contents were poured into a flask and dried. The solid was triturated with 25 mL of EtOAc at room temperature for 1 hour and then centrifuged. The solvent was decanted, and the residue was washed with 15 mL of EtOAc and centrifuged again. The washing and centrifugation procedure was then repeated twice. The residue was then dried to give 560 mg of a solid (84% purity).

[0119] 555 mg of the solid was suspended in MeOH (50 mL). A solution of NaOH (75 mg) in MeOH (1.5 mL) was added to give a clear solution. The solution was stirred for 10 min at room temperature and concentrated. The resulting brown foam was dissolved in MeOH (5 mL) and purified by column chromatography (C18; eluent, MeOH / water, 3:7 to 7:3) to give the product (99.5% purity). Yield: 110 mg (21%).

[0120] 1H NMR (300MHz, DMSO-d6) δ7.08 (dd, J=4.2, 2.5Hz, 1H), 6.93-6.58 (m, 4H), 6.52 -6.36(m, 2H), 6.34-6.06(m, 3H), 5.02(d, J=15.6Hz, 2H), 4.89(d, J=9.4Hz, 2H ), 4.66(d, J=15.3Hz, 1H), 3.75(d, J=2.7Hz, 3H), 3.58-3.36(m, 3H), 3.25(t, J =6.3Hz, 1H), 2.25(d, J=6.4Hz, 3H), 2.18(d, J=6.8Hz, 3H), 2.14-1.99(m, 9H). m / z (M-Na) = 533.18; 554.93.

[0121] 10.2 Formulations with API 10.2.1 Docetaxel-containing formulations A stock solution of docetaxel in methanol was mixed with a stock solution of compound 10 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to a docetaxel concentration of 0.5 mg / mL. The final weight ratio of docetaxel to micelle-forming agent was 1:5. Particle size and polydispersity index measurements were performed over time as shown in the table below. An increase in particle size and a slight decrease in polydispersity index were recorded over time (see table below). [Table 23]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 During the ceremony, R １ , R ２ , R ３ , R ４ and R ５ are each independently hydrogen, halogen, hydroxy, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy or C １－４ alkoxycarbonyl; R ６ is a halogen, C １－４ Alkyl, C １－４ Hydroxyalkyl, C ３－８ Cycloalkyl, C １－４ Alkylcarbonyl, C ２－４ Alkenylcarbonyl, C ３－８ Cycloalkylcarbonyl, aminocarbonyl-C １－４ Alkyl, —C(═NH)NH ２ and phenyl, wherein phenyl is optionally selected from the group consisting of halogen, hydroxy, C １－４ Alkyl, C １－４ substituted with one or more substituents selected from the group consisting of alkoxy and amino; R ７ Ha-(CR ８Ａ R ８Ｂ ) ｎ -X, benzyl-X or C ３－７ -cycloalkyl-(CR ８Ａ R ８Ｂ ) ｍ -X, n is an integer 2 or 3, m is an integer 1 or 2, and benzyl may optionally further comprise halogen, hydroxy, C １－４ Alkyl, C １－４ substituted with one or more substituents selected from the group consisting of alkoxy and amino; or R ６ and R ７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring, which is -(CR ８Ａ R ８Ｂ ) ｐ -X, phenyl-X or benzoyl-X, where p is an integer 1 or 2, and phenyl or benzoyl may optionally further be substituted with halogen, hydroxy, C １－４ Alkyl, C １－４ substituted with one or more substituents selected from the group consisting of alkoxy and amino; R ８Ａ and R ８Ｂ are each independently hydrogen, hydroxy, C １－４ Alkyl, C １－４ Alkoxy, —S(═O) ２ OH, —S(═O)OH and —P(═O)(OH) ２ selected from the group consisting of: X is -S(=O) ２ OH, -S(=O)OH or -P(=O)(OH) ２ or a pharmaceutically acceptable salt thereof.

2. R １ , R ２ , R ３ , R ４ and R ５ 10. The compound of claim 1, wherein each is independently selected from the group consisting of hydrogen, hydroxy, methyl, and methoxy.

3. R １ , R ２ and R ５ are each methyl, and R ３ is methoxy, and R ４ The compound of claim 1 or 2, wherein is hydrogen.

4. R ６ The compound according to any one of claims 1 to 3, wherein is methyl, 2-hydroxyethyl, cyclohexyl, prop-2-enoyl, 1,1-bis(hydroxymethyl)-2-hydroxyethyl or aminocarbonylmethyl.

5. R ７ Ha-(CR ８Ａ R ８Ｂ ) ｎ -X, n is an integer 2 or 3, and R ８Ａ and R ８Ｂ The compound of any one of claims 1 to 4, wherein each is independently selected from the group consisting of hydrogen and hydroxy.

6. R ７ The compound of any one of claims 1 to 4, wherein is benzyl-X, wherein the benzyl is further substituted with amino.

7. R ７ The compound of any one of claims 1 to 4, wherein is cyclohexyl-methyl-X.

8. R ６ and R ７ together with the nitrogen atom to which they are attached form a piperidine or piperazine ring, which is substituted with ethyl-X, phenyl-X or benzoyl-X.

9. X is -S(=O) ２ The compound according to any one of claims 1 to 8, wherein the aryl group is OH.

10. 10. The compound of claim 1 selected from the group consisting of: 【Chemistry 2】 【change】 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10.

12. 12. The pharmaceutical composition of claim 11, further comprising an active ingredient.

13. 13. The pharmaceutical composition of claim 12, wherein the active ingredient is a hydrophobic drug.

14. 13. The pharmaceutical composition of claim 12, wherein the active ingredient is a cytotoxic drug, preferably selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, doxorubicin and mitoxantrone.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein at least one compound according to any one of claims 1 to 10 and the active ingredient form a micelle.

16. A drug micelle comprising at least one compound according to any one of claims 1 to 10 and a drug.

17. 17. The drug micelle of claim 16, wherein the drug is a cytotoxic drug, preferably selected from the group consisting of docetaxel, paclitaxel, cabazitaxel, doxorubicin, and mitoxantrone.

18. 18. A pharmaceutical composition according to claim 14 or a drug micelle according to claim 17 for use in the treatment of cancer.

19. 11. A method for enhancing the effectiveness of a pharmaceutically active substance, wherein said substance is prepared in a micellar form together with a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

20. 11. A method for increasing the solubility of a pharmaceutically active substance, wherein said substance is prepared in micellar form with a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

21. 11. A method for improving the pharmacokinetic or pharmacodynamic properties of a pharmaceutically active substance, wherein said substance is prepared in a micellar form together with a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

22. 11. A method for improving the storage properties of a pharmaceutically active substance, wherein said substance is prepared in micellar form together with a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

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